Soft tissue augmentation material

ABSTRACT

A permanent, biocompatible material for soft tissue augmentation. The biocompatible material comprises a matrix of smooth, round, finely divided, substantially spherical particles of a biocompatible ceramic material, close to or in contact with each other, which provide a scaffold or lattice for autogenous, three dimensional, randomly oriented, non-scar soft tissue growth at the augmentation site. The augmentation material can be homogeneously suspended in a biocompatible, resorbable lubricious gel carrier comprising a polysaccharide. This serves to improve the delivery of the augmentation material by injection to the tissue site where augmentation is desired. The augmentation material is especially suitable for urethral sphincter augmentation, for treatment of incontinence, for filling soft tissue voids, for creating soft tissue blebs, for the treatment of unilateral vocal cord paralysis, and for mammary implants. It can be injected intradermally, subcutaneously or can be implanted.

This is a divisional of application Ser. No. 08/159,071, filed Nov. 29,1993, which is a file wrapper continuation of application Ser. No.07/999,411 filed Jan. 21, 1993, now abandoned, which is acontinuation-in-part of U.S. Ser. No. 833,874 filed Feb. 11, 1992, nowabandoned.

FIELD OF THE INVENTION

This invention relates to biocompatible compositions for soft tissueaugmentation more specifically urethral sphincter augmentation fortreatment of incontinence, for filling soft tissue voids or creatingsoft tissue blebs, for mammary implants, and for the treatment ofunilateral vocal cord paralysis.

BACKGROUND OF THE INVENTION

Examples of biocompatible materials that have been proposed for use inaugmenting soft tissue in the practice of plastic and reconstructivesurgery, include collagen, gelatin beads, beads of natural or syntheticpolymers such as polytetrafluoroethylene, silicone rubber and varioushydrogel polymers, such as polyacrylonitrile-polyacrylamide hydrogels.

Most often, the biomaterials are delivered to the tissue site whereaugmentation is desired by means of an injectable composition whichcomprises the biomaterial and a biocompatible fluid that acts as alubricant to improve the injectability of the biomaterial suspension.The injectable biomaterial compositions can be introduced into thetissue site by injection from a syringe intradermally or subcutaneouslyinto humans or other mammals to augment soft tissue, to correctcongenital anomalies, acquired defects or cosmetic defects. They mayalso be injected into internal tissues such as tissue definingsphincters to augment such tissue in the treatment of incontinence, andfor the treatment of unilateral vocal cord paralysis.

U.K Patent Application No. 2,227,176 to Ersek et al, relates to amicroimplantation method for filling depressed scars, unsymmetricalorbital floors and superficial bone defects in reconstructive surgeryprocedures using microparticles of about 20 to 3,000 microns which maybe injected with an appropriate physiologic vehicle and hypodermicneedle and syringe in a predetermined locus such as the base ofdepressed scars, beneath skin areas of depression and beneathperichondrium or periosteum in surface irregularities of bone andcartilage. Textured microparticles can be used, including silicone,polytetrafluoroethylene, ceramics or other inert substances. In thoseinstances wherein the requirement is for hard substances, biocompatiblematerial such as calcium salts including hydroxyapatite or crystallinematerials, biocompatible ceramics, biocompatible metals such asstainless steel particles or glass may be utilized. Appropriatephysiological vehicles have been suggested, including saline, variousstarches, polysaccharides, and organic oils or fluids.

U.S. Pat. No. 4,803,075 to Wallace et al, relates to an injectableimplant composition for soft tissue augmentation comprising an aqueoussuspension of a particulate biocompatible natural or synthetic polymerand a lubricant to improve the injectability of the biomaterialsuspension.

U.S. Pat. No. 4,837,285 to Berg et al, elates to a collagen-basedcomposition for augmenting soft tissue repair, wherein the collagen s inthe form of resorbable matrix beads having an average pore size of about50 to 350 microns, with the collagen comprising up to about 10% byvolume of the beads.

U.S. Pat. No. 4,280,954 to Yannas et al, relates to a collagen-basedcomposition for surgical use formed by contacting collagen with amucopolysaccharide under conditions at which they form a reactionproduct and subsequently covalently crosslinking the reaction product.

U.S. Pat. No. 4,352,883 to Lim discloses a method for encapsulating acore material, in the form of living tissue or individual cells, byforming a capsule of polysaccharide gums which can be gelled to form ashape retaining mass by being exposed to a change in conditions such asa pH change or by being exposed to multivalent cations such as calcium.

Namiki, "Application of Teflon Paste for Urinary Incontinence-Report ofTwo Cases", Urol. Int., Vol. 39, pp. 280-282, (1984), discloses the useof a polytetrafluoroethylene paste injection in the subdermal area totreat urinary incontinence.

Drobeck et al, "Histologic Observation of Soft Tissue Responses toImplanted, Multifaceted Particles and Discs of Hydroxylapatite", Journalof Oral Maxillofacial Surgery, Vol. 42, pp. 143-149, (1984), disclosesthat the effects on soft tissue of long and short term implants ofceramic hydroxylapatite implanted subcutaneously in rats andsubcutaneously and subperiosteally in dogs. The inventions consisted ofimplanting hydroxylapatite in various sizes and shapes for time periodsranging from seven days to six years to determine whether migrationand/or inflammation occurred.

Misiek et al., "Soft Tissue Responses to Hydroxylapatite Particles ofDifferent Shapes", Journal of oral Maxillofacial Surgery, Vol. 42, pp.150-160, (1984), discloses that the implantation of hydroxylapatite inthe form of sharp edged particles or rounded particles in the buccalsoft tissue pouches produced inflammatory response at the implant siteswith both particle shapes. Each of the particles weighed 0.5 grams.However, inflammation resolved at a faster rate at the sites implantedwith the rounded hydroxylapatite particles.

Shimizu, "Subcutaneous Tissue Responses in Rats to Injection of FineParticles of Synthetic Hydroxyapatite Ceramic", Biomedical Research,Vol. 9, No. 2, pp. 95-111 (1988), discloses that subcutaneous injectionsof fine particles of hydroxyapatite ranging in diameter from about 0.65to a few microns and scattered in the tissue were phagocytized bymacrophages in extremely early stages. In contrast, larger particlesmeasuring several microns in diameter were not phagocytized, but weresurrounded by numerous macrophages and multinucleated giant cells. Itwas also observed that the small tissue responses to hydroxyapatiteparticles were essentially a non-specific foreign body reaction withoutany cell or tissue damage.

R. A. Appell, "The Artificial urinary Sphincter and PeriurethralInjections", Obstetrics and Gynecology Report. Vol. 2, No. 3, pp.334-342, (1990), is a survey article disclosing various means oftreating urethral sphincteric incompetence, including the use ofinjectables such as polytetrafluoroethylene micropolymer particles ofabout 4 to 100 microns in size in irregular shapes, with glycerin andpolysorbate. Another periurethral injectable means consists of highlypurified bovine dermal collagen that is crosslinked with glutaraldehydeand dispersed in phosphate-buffered physiologic saline.

Politano et al., "Periurethral Teflon Injection for UrinaryIncontinence", The Journal of Urology, Vol. 111, pp. 180-183 (1974),discloses the use of polytetrafluoroethylene paste injected into theurethra and the periurethral tissues to add bulk to these tissues torestore urinary control in both female and male patients having urinaryincontinence.

Malizia et al, "Migration and Granulomatous Reaction After PeriurethralInjection of Polytef (Teflon)", Journal of the American MedicalAssociation, Vol. 251, No. 24, pp. 3277-3281, Jun. 22-29 (1984),discloses that although patients with urinary incontinence have beentreated successfully by periurethral injection ofpolytetrafluoroethylene paste, a study in continent animals demonstratesmigration of the polytetrafluoroethylene particles from the inspectionsite.

Claes et al, "Pulmonary Migration Following PeriurethralPolytetrafluoroethylene Injection for Urinary Incontinence", The Journalof Urology, Vol. 142, pp. 821-2, (September 1989), confirms the findingof Malizia in reporting a case of clinically significant migration ofpolytetrafluoroethylene paste particles to the lungs after periurethralinjection.

Ersek et al, "Bioplastique: A New Textured Copolymer MicroparticlePromises Permanence in Soft-Tissue Augmentation", Plastic andReconstructive Surgery, Vol. 87, No. 4, pp. 693-702, (April 1991),discloses the use of a biphasic copolymer made of fully polymerized andvulcanized methylmethylpoly-siloxane mixed with a plasdore hydrogel, andused in reconstructing cleft lips, depressed scars of chicken pox andindentations resulting from liposuction, glabella frown wrinkles andsoft tissue augmentation of thin lips. The biphasic copolymer particleswere found to neither migrate nor become absorbed by the body weretextured and had particle sizes varying from 100 to 600 microns.

Lemperle et al. "PMMA Microspheres for Intradermal Implantation: Part I.Animal Research", Annals of Plastic Surgery, Vol. 26, No. 1, pp. 57-63,(1991), discloses the use of polymethylmethacrylate microspheres havingparticle sizes of 10 to 63 microns in diameter used for correction ofsmall deficiencies within the dermal corium to treat wrinkles and acnescars.

Kresa et al, "Hydron Gel Implants in Vocal Cords", Otolaryngology Headand Neck Surgery, Vol. 98. No. 3, pp. 242-245, (March 1988), discloses amethod for treating vocal cord adjustment where there is insufficientclosure of the glottis which comprises introducing a shaped implant of ahydrophilic gel that has been previously dried to a glassy, hard state,into the vocal cord.

Hirano et al, "Transcutaneous Intrafold Injection for Unilateral VocalCord Paralysis: Functional Results", Ann Otol. Rhinol. Laryngol., Vol.99, pp. 598-604 (1990), discloses the technique of transcutaneousintrafold silicone injection in treating glottic incompetence caused byunilateral vocal fold paralysis. The silicone injection is given under alocal anesthetic with the patient in a supine position, wherein theneedle is inserted through the cricothyroid space.

Hill et al, "Autologous Fat Injection for Vocal Cord Medialization inthe Canine Larynx", Laryngoscope, Vol. 101, pp. 344-348 (April 1991),discloses the use of autologous fat as an alternative to Teflon®collagen as the implantable material in vocal cord medialization, with aview to its use as an alternative to non-autologous injectable materialin vocal cord augmentation.

Mikaelian et al, "Lipoinjection for Unilateral Vocal Cord Paralysis",Laryngoscope, Vol. 101, pp. 4654-68 (May 1991), discloses that thecommonly used procedure of injecting Teflon® paste to improve thecaliber of voice in unilateral vocal cord paralysis has a number ofdrawbacks, including respiratory obstruction from overinjected Teflon®and unsatisfactory voice quality. In this procedure, lipoinjection offat commonly obtained from the abdominal wall appears to impart a softbulkiness to the injected cord while allowing it to retain its vibratoryqualities. The injected fat is an autologous material which can beretrieved if excessively overinjected.

Strasnick et al, "Transcutaneous Teflon® Injection for Unilateral VocalCord Paralysis: An Update", Laryngoscope, Vol. 101, pp. 785-787 (July1991), discloses the procedure of Teflon® injection to restore glotticcompetence in cases of paralytic dysphonia.

SUMMARY OF THE INVENTION

In accordance with the present invention, there is provided a permanent,biocompatible material for soft tissue augmentation, and methods for itsuse. The biocompatible material comprises a matrix of smooth, rounded,substantially spherical, finely divided particles of a biocompatibleceramic material, close to or in contact with each other, which providea scaffold or lattice for autogenous, three dimensional, randomlyoriented, non-scar soft tissue growth at the augmentation site. Theaugmentation material can be homogeneously suspended, for example, in abiocompatible, resorbable lubricious gel carrier comprising, e.g., apolysaccharide. This serves to improve the delivery of the augmentationmaterial by injection to the tissue site where augmentation is desired.The augmentation material is especially suitable for urethral sphincteraugmentation, for treatment of incontinence, for filling soft tissuevoids, for creating soft tissue blebs, for the treatment of unilateralvocal cord paralysis, and for mammary implants. It can be injectedintradermally or subcutaneously or can be implanted.

DESCRIPTION OF THE DRAWINGS

In the accompanying drawings,

FIG. 1 is a photomicrograph of smooth, round calcium hydroxyapatiteparticles at 40× magnification;

FIG. 2 is a photomicrograph of a histological section of rabbit tissueat 50× magnification showing fibroblastic infiltration.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

In instances of urinary incontinence, such as stress incontinence inwomen, or after a prostatectomy in men, it is necessary to compress theurethra to assist the sphincter muscle in closing to avoid leakage ofurine from the bladder.

The soft tissue augmentation material of the present invention comprisesan injection system which can be used to add bulk and localizecompression to the sphincter muscle/urethra, thereby reducing the lumensize through one or more injections of the augmentation material andthus substantially reduce or eliminate urinary stress incontinence dueto incompetent sphincters in females and males.

The augmentation material can also be used in filling and smoothing outsoft tissue defects such as pock marks or scars. Further use for theaugmentation material can be for intracordal injections of the laryngealvoice generator by changing the shape of this soft tissue mass. Theprocedure involves delivering the augmentation material to the site oftreatment, preferably by injection.

The augmentation material can also be used for mammary implants, and canbe encased in a suitable shell made of a polymeric material such aspolyurethanes, ethylene-propylene diene monomers, ethylene-propylenerubbers, polyolefins, and silicone elastomers. It can also be usedwithout a shell since the augmentation material does not migrate andremains in a particular area or bolus.

The inventive augmentation material comprises smooth rounded,substantially spherical, particles of a ceramic material. The term"substantially spherical" refers to the fact that while some of thepresent particles may be spheres, most of the particles of the presentinvention are sphere-like in their shapes i.e., they are spheroidal.FIG. 1 is illustrative of these spheroidal or substantially sphericalcharacteristics. The terms "rounded" or "smooth, rounded" as used hereinrefers to the fact even though the present particles are not perfectspheres, they do not have any sharp or angular edges. The particles mustbe sufficiently large so as to avoid phagocytosis, as is furtherdiscussed below. As an upper limit the particles can be any sizesuitable for the desired soft tissue augmentation. However, it isunderstood that for introduction by injection the upper limit onparticle size will be dictated by the particular injection equipmentemployed. That is, the particles must be sufficiently small so as toavoid aggregation and clogging of the syringe when being injected. Atypical range for injection is from about 35 to 150 microns, preferablyin a narrow particle size range extending not more than about 35microns, and more preferably extending not more than about 10 to 30microns, and most preferably having substantially equivalent particlesizes. For example, the ceramic material can have a uniform particlesize distribution of about 35 to 65 microns, or 75 to 100 microns or 100to 125 microns. These are meant to be exemplary and not limiting. Othernarrow particle size ranges within the overall size range of 35 to 150microns can also be used. In discussing these ranges, it should beunderstood that as a practical matter, a small amount of particlesoutside the desired range may be present in a sample of the presentaugmentation material. However, most of the particles in any givensample should be within the desired range. Preferably, 90% of theparticles are within the desired range and most preferably 95-99% arewithin the range.

The finely divided ceramic augmentation material is substantiallynon-resorbable so that repetitious corrections are riot necessary. By"substantially non-resorbable" is meant that although some dissolutionof the augmentation material may take place over time, it issufficiently slow so as to allow for replacement with growing tissuecells. There is no antigenic response because there are no amino acidsas in collagen and fibrinogen. The ceramic material is highlybiocompatible and can be injected through an 18 gauge or smaller openingsyringe.

The preferred ceramic material is calcium hydroxyapatite, also known asbasic calcium orthophosphate, or calcium hydroxylapatite, and is thenatural mineral phase of teeth and bones. As an implant material,granular calcium hydroxyapatite, which is a sintered polycrystallinecomposite of calcium phosphate, has proven to be highly compatible intissue.

One method for preparing dense, rounded or substantially sphericalceramic particles such as calcium hydroxyapatite is by spray drying aslurry of about 20 to 40 weight % submicron particle size calciumhydroxyapatite. This material is commercially available or can beprepared by means known in the art such as by low temperaturecrystallization methods, hydrothermal crystallization methods,solid-solid reaction and the like. The slurry can also includeprocessing additives such as wetting agents and binders, on the order ofabout 1 to 5 weight %. Suitable wetting agents include polysorbate,sodium oxalate, ammonium polyelectrolyte. Suitable binders includepolyvinyl alcohol, dextrin or carbowax.

The slurry is spray dried by pumping it through a nozzle to formglobules that are forced through a column of heated air to remove themoisture. The agglomerated particles dry in substantially sphericalshape and are collected at one end of the heated column.

The substantially spherical particles are then sintered in a crucible attemperatures of about 1050 to 1200° C. for at least one hour. Tominimize further agglomeration, a presintering operation at about 800 to1000° C. for about one hour can be employed.

After the presintering operation, the globular particles can be agitatedor rolled to prevent the individual particles from sticking or clumpingtogether. A rotary calcining furnace can be used for this purpose. Thistype of furnace rotates so that the agglomerated particles roll over oneanother during the sintering process thereby minimizing the clumpingtogether of the particles. A commercial source of such spray driedparticles is CeraMed Corp., Lakewood, Colo.

An alternative method for forming dense, spherical particles is byrotary agglomeration, wherein the fine, submicron ceramic particles,such as calcium hydroxyapatite, are placed on a large diameter rotatingbowl that is at least about 3 feet in diameter.

The bowl is rotated on its axis at an angle of approximately thirtydegrees, with its speed and angle of rotation adjusted so that thesubmicron particles roll across the face of the bowl. A fine spray ofbinder solution, such as those described above, is then sprayed on theparticles at a rate which just wets the particles. The rolling actionacross the face of the bowl and the addition of the binder solutioncauses the particles to form small rolling agglomerates that grow insize as the operation continues. The operation is comparable to forminga large ball of snow by rolling a small snowball down a hill. Theoperating conditions, such as the size of bowl, speed of rotation, angleof rotation and amount of spray used which define the size and densityof the agglomerates formed, are well known to those skilled in the art.The agglomerated spherical particles can then be sintered in a mannersimilar to the spray dried agglomerates.

The resulting sintered spherical particles can then be separated andclassified by size by means of well known sieving operations throughspecifically sized mesh screens. The particle size distribution anddensity can also be evaluated to ensure suitability for a particularapplication. A commercial source of such rotary agglomerated particlesis CAM Implants, Leiden, The Netherlands.

Further surface refining or smoothing can be accomplished by a millingoperation, such as ball milling. Extra mini-grinding media can be used,but to minimize contamination, the spherical particles can be milled onthemselves. This can be done in a standard jar mill or an inclinedrotation mill by adding sufficient amounts of purified water to theparticles to ensure that the particles roll evenly over each other. Thiscan be done for long periods such as several days to make the surfacesmooth on the round agglomerates. If the starting agglomerates are notround, they can be made smooth but not round by rolling. Irregularlyshaped agglomerates, although having a smooth surface, can jam, obstructor significantly increase the injection force on a syringe needle wheninjected into tissue.

The agglomerated spherical particles can also be washed free of smallparticles by using an inclined rotation mill. This can be done byplacing the agglomerates in the mill with purified water and rolled fora sufficient time, such as one hour. The supernate is then poured offand more purified water is added. The process is repeated until thesupernate is relatively clear after a rotating cycle, and usually takesabout three or four operations.

The methods described above are suitable for any ceramic materials whichmay be employed.

A smooth surface on the individual round, spherical particles isimportant to reduce and minimize surface porosity. Surface smoothnesscan be improved by finishing operations known in the art, such assurface milling and the like. It is preferred that such smoothingoperations be capable of minimizing surface irregularities on theindividual particles so that the surface appears similar to that of asmooth round bead when viewed under a microscope at 40× magnification.This is apparent from FIG. 1, which is a photomicrograph of calciumhydroxyapatite particles having a particle size distribution of 38 to 63microns. The smooth, round substantially spherical and non-poroussurface is readily evident.

The ceramic particles are preferably smooth, hard, rounded particles,having a density on the order of about 75 to 100%, and preferably about95 to 100% of the theoretical density of desired ceramic material, e.g.,calcium hydroxyapatite. The finishing operations can also minimize thesurface porosity of the calcium hydroxyapatite particles to less thanabout 30%, and preferably less than about 10%. This is preferred,because by minimizing surface porosity, particles with smooth surfacescan be obtained, thereby eliminating jagged, irregular surfaces andmaximizing the ability of the smooth, round particles to flow easily incontact with each other.

Although this invention is described in terms of calcium hydroxyapatite,other suitable materials useful herein include, but are not limited to,calcium phosphate-based materials, alumina-based materials and the like.Examples include, but are not limited to, tetracalcium phosphate,calcium pyrophosphate, tricalcium phosphate, octacalcium phosphate,calcium fluoroapatite, calcium carbonate apatite, and combinationsthereof. Other equivalent calcium based compositions can also be usedsuch as calcium carbonate, and the like.

As noted, the individual ceramic particles used in the present inventionhave a generally smooth, round, preferably spherical shape, in contrastto particles with more textured porous surfaces or openings, and havingjagged, irregular shapes or shapes with straight edges. The smooth roundshape enables the ceramic particles to be more easily extruded and toflow with reduced friction from a syringe into the tissue site wheresoft tissue augmentation is desired. Once at the tissue site, theceramic particles provide a matrix or scaffolding for autogenous tissuegrowth.

As mentioned above, particle sizes in the range of about 35 to 150microns are optimal to minimize the possibility of particle migration byphagocytosis and to facilitate injectability. Phagocytosis occurs wheresmaller particles on the order of 15 microns or less become engulfed bythe cells and removed by the lymphatic system from the site where theaugmentation material has been introduced into the tissues, generally byinjection.

At the lower end, particles greater than 15 microns and typically 35microns or above are too large to be phagocytosized, and can be easilyseparated by known sizing techniques. Thus, it is relatively simple toproduce the narrow or equivalent particle size ranges that are mostdesirable for use in this invention.

It is also desirable to use a narrow or equivalent particle size rangeof ceramic particles due to the fact that a distribution of such smooth,round, substantially spherical particles reduces friction, andfacilitates the ease of injecting the particles by needle from a syringeinto the skin tissue at the desired augmentation site. This is incontrast to the use of the more porous, textured, irregularly shapedparticles which tend to increase the frictional forces, and are muchmore difficult to deliver by injection.

As discussed above, the particle size distribution, or range of particlesizes of the ceramic material within the overall range of 35 to 150microns is preferably minimized to a more narrow or equivalent particlesize range. This maximizes the intraparticle void volume, orinterstitial volume, into which autogenous tissue growth, stimulated bythe presence of the augmentation material, can occur. A greaterinterstitial volume exists between particles that are equivalent insize, compared with particles having a variable size distribution. Inthe context of this invention, the interstitial volume is the void spaceexisting between particles of the augmentation material that are closeto or in contact with each other.

For example, in crystalline lattice structures such as face centeredcubic, body centered cubic and simple cubic, the percentage ofinterstitial void space, known as the atomic packing factor. is 26%,33%, and 48%, respectively. This is independent of the diameter of theatom or in this case, the particle. Since the ceramic particles neverpack as tightly as the atoms in a crystalline lattice structure, thevoid volume would be even greater, thereby maximizing the growth ofautogenous tissue.

To extend the analogy of the crystalline structure a step further, theinterstitial opening defines the maximum size that a particle can fitinto a normally occurring void space in the structure. The largestinterstitial space is about 0.4 times the size of the mean ceramicparticle in the particle size distribution.

Thus, if the particle size distribution is about 35 to 65 microns, themean particle size would be 50 microns. The largest interstitial spacewould be 50×0.4=20 microns. Since no 20 micron size particles exist inthe distribution, packing would be minimized. Similarly, with a particlesize distribution of 75 to 125 microns, the mean particle size is 100microns, and the largest interstitial space would be 100×0.4=40 microns.Since no 40 micron particles exist in the distribution, packing wouldalso be minimized. Therefore, if the ceramic particles are restricted toa narrow particle size range or equivalent size distribution, there willbe a maximizing of the void volume into which the autogenous tissue cangrow.

Other suitable particle size distribution ranges include 35 to 40microns, 62 to 74 microns and 125 to 149 microns, however, any othercorrespondingly narrow ranges can also be used.

In contrast, where there is a wide particle size distribution, there isa greater tendency for the particles to become densely packed since thesmaller particles tend to group or migrate into the spaces between thelarger particles. This results in less interstitial space availablebetween the particles for the autogenous tissue such as fibroblasts andchondroblasts to infiltrate and grow.

The tissue growth where the augmentation material has a wide particlesize distribution is denser and harder, because of the packing effectwhich occurs between the large and small particles. In contrast, the useof particles equivalent in size, or having a narrow particle size rangeof uniformly distributed particles increases the intraparticle voidvolume. This enables a maximum amount of autogenous or three dimensionalrandomly oriented non-scar soft tissue ingrowth to infiltrate the spaceor interstices between the particles. The more interstitial space thatis available makes it more likely that the subsequent autogenous tissuegrowth stimulated by the presence of the augmentation material into thematrix or scaffolding provided by the augmentation material will closelyresemble the original tissue in the immediate vicinity or locus ofaugmentation.

The process of soft tissue augmentation can occur by injecting orimplanting the biocompatible augmentation material comprising thedesired particle sizes of the desired ceramic material into the tissueat the desired augmentation site to form a bleb or blister. Thesubsequent autogenous tissue growth into the matrix provided by theaugmentation material will most closely resemble the surrounding tissuein texture and properties. This is in contrast to that which occursusing known state-of-the-art procedures, where foreign body response isknown to occur, typically with Teflon® augmentation where granulomashave been known to form.

Foreign body response is the body reaction to a foreign material. Atypical foreign body tissue response is the appearance ofpolymorphonuclear leukocytes near the material followed by macrophages.If the material is nonbioreactive, such as silicone, only a thincollagenous encapsulation tissue forms. If the material is an irritant,inflammation will occur and this will ultimately result in granulationtissue formation. In the case of ceramic materials such as calciumhydroxyapatite, there is excellent biocompatibility resulting in tissuecell growth directly on the surface of the particles with a minimum of,or substantially no encapsulation.

Autogenous tissue is defined herein as any tissue at a specific definedlocation in the body, whose growth is stimulated by the presence of thematrix of the biocompatible augmentation material at the site where softtissue augmentation is desired. Such autogenous tissue from augmentationin the area of the urethral sphincter would resemble existing tissue inthe urethral sphincter. Autogenous tissue from augmentation in thelarynx would resemble existing tissue in the glottis where the vocalapparatus of the larynx is located. Autogenous tissue from breastaugmentation would resemble existing tissue in the mammaries, and so on.Autogenous tissue in the case of intradermal injections would resemblethe dermis. In a similar manner, the augmentation material, by providinga three dimensional lattice can be used in surgical incisions or traumato avoid linear, layered contractile scar formation.

As discussd above, the calcium hydroxyapatite particles used as theaugmentation material are biocompatible and substantiallynon-resorbable. Thus, the soft tissue augmentation procedure ispermanent. Moreover, the use of calcium hydroxyapatite does not requirethe strict rigorous precautions that are necessary when using otheraugmentation materials such as collagen which need refrigeration forstorage, shipping and antigenicity testing.

The rounded, spherical smooth calcium hydroxyapatite particles enhancethe biocompatibility to the autogenous tissue response into the particlematrix and substantially eliminates the potential for calcification.Jagged or irregular particles can irritate tissue and can causecalcification. In addition, surface porosity on the order of about 30volume % or greater can also cause calcification because of the relativestability of the pores in the particles. Smooth, round, substantiallynon-porous particles maintain movement in the tissue. Thus, theautogenous tissue grown in the particle matrix where movement ismaintained, does not calcify. In contrast, the porous sections of theindividual particles are stationary relative to the particle, thustissue infiltration into the pores is not subject to movement andcalcification can occur.

The particulate ceramic material can be suspended in a biocompatible,resorbable lubricant, such as a cellulose polysaccharide gel to improvethe delivery of the augmentation material by injection to the tissuesite where augmentation is desired. Preferably, the gel comprises water,glycerin and sodium carboxymethylcellulose. The gel enables the ceramicparticles to remain in suspension without settling for an indefiniteperiod of time until used, more specifically, at least about 6 months.Other suitable lubricant compositions known in the art can also beemployed.

In general, the ratio of water to glycerin in the gel can vary fromabout 10 to 100:90 to 0, preferably about 20 to 90:80 to 10, and mostpreferably about 25 to 75:75 to 25, respectively.

The viscosity of the gel can vary from about 20,000 to 200,000centipoise, preferably about 40,000 to 100,000 centipoise as measuredwith a Brookfield Viscometer with RU#7 spindle at 16 revolutions perminute (rpm). It has been found that with gel viscosities below about20,000 centipoise the particles do not remain in suspension, and withgel viscosities above about 200,000 centipoise, the gel becomes tooviscous for convenient mixing.

The sodium carboxymethycellulose included in the gel has a highviscosity rating. More specifically, the sodium carboxymethylcellulosepreferably has a viscosity of about 1000 to 2800 centipoise in a 1%aqueous solution and can vary from about 0.25 to 5 weight %, preferably1.25 to 3.25% of the combined water and glycerin in the gel.

Other polysaccharides can also be included such as cellulose, agarmethylcellulose, hydroxypropyl methylcellulose, ethylcellulose,microcrystalline cellulose, oxidized cellulose, and other equivalentmaterials. Unexpectedly, formulating the augmentation particles of thepresent invention, particularly the calcium hydroxyapatite with sodiumcarboxymethylcellulose, provides a change in the surface morphology ofthe particles which is believed to enhance the physical andbiocompatible properties of the material.

The gel is prepared by mixing the gel components at ambient conditionsuntil all components are in solution. It is preferable to combine theglycerin and NaCMC components together first until a thoroughly mixedsolution is obtained. The glycerin/NaCMC solution is then mixed togetherwith the water until all components are in solution to form the gel.After the gel components have been thoroughly mixed, the gel is allowedto set for minimum of 4 hours, after which viscosity readings are takento ensure that the gel has the desired viscosity.

While any lubricant can be employed, it has been found that certainmaterials, e.g., polysorbate surfactants, pectin, chondroitin sulfateand gelatin, are not able to suspend the ceramic particles for anindefinite amount of time and allow further processing or be as easy toinject in the same manner as the sodium carboxymethylcellulose. Thus,the sodium caarboxymethylcellulose materials are preferred.

The polysaccharide gel is biocompatible and able to maintain theparticles of ceramic material in what amounts to a substantiallypermanent state of suspension so that the ceramic particulate/gelcomposition comprising the augmentation material does not require mixingbefore use. As already noted, the lubricious nature of thepolysaccharide gel reduces the frictional forces generated bytransferring the augmentation material from a syringe by injection intothe tissue site.

In addition, the polysaccharides do not generate an antigenic responseas do products containing amino acids. The polysaccharide gel is readilysterilizable and stable at ambient conditions and does not needrefrigeration for storage and shipment, in contrast to systems used withcollagen containing materials.

Sterilization is ordinarily accomplished by autoclaving at temperatureson the order of about 115° C. to 130° C., preferably about 120° C. to125° C. for about 30 minutes to 1 hour. Gamma radiation is unsuitablefor sterilization since it tends to destroy the gel. It has also beenfound that sterilization generally results in reduction of itsviscosity. However, this does not adversely affect the suspension andtherefore the extrusion force of the augmentation material through asyringe, nor does it affect the ability of the gel to hold the calciumhydroxyapatite particles in suspension, as long as the prescribedviscosity ranges for the gel are maintained.

After injection of the augmentation material into the tissue, thepolysaccharide gel is harmlessly resorbed by the tissue, leaving thenon-resorbable calcium hydroxyapatite matrix in place in the particulararea or bolus, where it has been found to remain without migrating toother areas of the body. It generally takes an average of about 2 weeksfor the polysaccharide to completely resorb.

FIG. 2 shows a histological section of rabbit tissue at 50×magnification which has been infiltrated with autogenous threedimensional, randomly oriented, non-scarring soft muscle tissue as aresult of an injection of calcium hydroxyapatite particles having auniform particle size distribution of 38 to 63 microns. Thephotomicrograph shows growth after 12 weeks. The histological sectionalso demonstrates the biocompatibility of the calcium hydroxyapatite asthe cells grow on the surface of the particles with minimal orsubstantially no foreign body response.

It has been found that the amount of calcium hydroxyapatite particles inthe augmentation material can vary from about 15% to 50% by volume, andpreferably about 25% to 47.5% and most preferably about 35% to 45% byvolume of the total augmentation material, comprising the gel and theceramic particles.

Preparations having above 50 volume % ceramic particles become viscousand care should be taken as to the selection of injection apparatus. Asa lower limit the augmentation material of this invention shouldobviously contain a sufficient volume of ceramic particles to provide aneffective base for tissue autogenous tissue growth. For mostapplications this is at least 15 volume %. By maintaining a volume % ofabout 35 to 45%, a correction factor of about 1:1 can be achieved, thatis, the volume of autogenous tissue growth is roughly equivalent to thevolume of particles introduced and shrinkage or expansion at the site ofthe soft tissue augmentation does not generally occur.

Also, within these parameters, the augmentation material can easily beinjected through an 18 gauge or smaller syringe intradermally orsubcutaneously. Because of the reduced frictional forces necessary todeliver the biocompatible augmentation material by injection to thedesired tissue site, the size of the syringe used to transfer or injectthe biocompatible augmentation material can be significantly reduced.This substantially eliminates the possibility of creating a needle trailthrough which leakage of the augmentation material from the injectionsite can occur after withdrawing the injection needle. Thus, thesyringes used to inject the augmentation material can have reducedopenings of less than 1,000 microns in diameter to a minimum of about178 microns or less.

For example, an 18 gauge syringe having a diameter of about 838 microns,or a 20 gauge syringe having a diameter of about 584 microns, or a 22gauge syringe having a diameter of about 406 microns, and even a 28gauge syringe having a diameter of about 178 microns can be used,depending on the tissue site where augmentation is needed.

The lubricious suspension of augmentation material is prepared by simplymixing the desired mount of ceramic particles with the lubricious geluntil a uniform, homogeneous suspension is reached. The consistency ofthe ceramic particles suspended in the lubricious gel is comparable tostrawberry preserves, wherein the seeds and other solid parts of thestrawberry, for all practical purposes, are comparable to the ceramicparticles and remain substantially permanently suspended in the jellypreserve matrix.

The suspension of ceramic material in the lubricious gel is so stable,that centrifugation at forces on the order of 500 g's, that is, 500times the force of gravity generally do not affect the stability of thesuspension or cause it to settle out. The tendency, if any, forparticles to settle out over a period of time would appear more likelyto occur with the larger particle sizes on the order of 125 microns orlarger. Thus, remixing the augmentation material at the time ofinjection or implantation is ordinarily not necessary. In addition, thepolysaccharide gel lubricates the suspended ceramic particles so thatthe injection force on the syringe can be minimized when injecting theaugmentation material.

The following examples show specific embodiments of the invention. Allparts and percentages are by weight unless otherwise noted.

EXAMPLE 1 Preparation of the Gel

A mixture of 25% glycerin, 75% water, and 2.25% NaCMC (based on thecombined weight of the water and glycerin) is prepared in the followingmanner:

87.90 g of glycerin and 7.91 g of NaCMC are combined in a vessel largeenough to mix total mass. The mixture is then slowly added to 263.71 gof agitating water in a container large enough for batch size andallowed to mix, utilizing an electric mixer, for 30 minutes at a mediumspeed. The gel is allowed to set for a minimum of four hours.

EXAMPLE 2 Preparation of the Augmentation Composition

Aqueous glycerin/NaCMC gel (38.52 g, prepared in Example 1) are placedin a mixing container large enough for batch size. Smooth, roundedsubstantially spherical CaHA particles (74.86 g) having a uniformparticle size of 37 to 63 microns are thoroughly blended, utilizing anelectric mixer, for five minutes at a low speed until all the particlesare homogeneously distributed in a uniform suspension in the gel.

EXAMPLE 3

In most instances it takes relatively little force to inject or extrudethe augmentation composition, comprising the polysaccharidegel/particulate calcium hydroxyapatite suspension, into the air sincethere is relatively little resistance. However, greater forces werenecessary to inject the augmentation composition into tissue, and thisforce is significantly influenced by the shape of the particulatematerial. This was exemplified by preparing sterilized suspensions ofpolysaccharide gel made of 75% water, 25% glycerin, and 2.25% sodiumcarboxymethylcellulose (based on the combined weight of the water andglycerin) with various volume percents of calcium hydroxyapatiteparticles having different shapes, following the procedure of Example 2.The thus prepared suspensions were placed in standard 3 cubic centimetersyringes. The force applied to the plunger to extrude the polysaccharidegel/particulate suspension at a rate of one inch per minute through an18 gauge needle was then measured. The force was also measured with theneedle inserted into turkey gizzard tissue as an analogy as it would beused clinically. The spray dried particles of calcium hydroxyapatite,regardless of their shape, had a smooth, uniform appearance undermicroscopic examination at 40× magnification. The particles wereuniformly distributed within the range of particle sizes. The resultsare tabulated in Table 1, which follows:

                  TABLE 1    ______________________________________    Calcium Hydroxyapatite Particles in the Gel                     Volume.                            Force, lbs    Size, Microns              Particle Shape                           % Solids Air   Tissue    ______________________________________    38 to 63  Spherical/Smooth                           35       4.5   6.0    38 to 63  Spherical/Smooth                           40       5.9   7.2    38 to 63  Irregular    40        8.0*  9.6*     74 to 100              Irregular/Smooth                           37       5.5   >30     74 to 100              Irregular/Smooth                           41       >30   >30     74 to 100              Spherical/Smooth                           42       4.8   5.5    ______________________________________     *Average. Inconsistent results due to complete obstruction of needle that     sporadically occurred during the tests., requiring replacement of needle.

This data correlated with animal experimentation where it was notpossible to inject irregular particles into tissue even when the percentsolids were reduced below 25 volume % or a 16 gauge needle was used.

EXAMPLE 4

Sterilized samples of polysaccharide gel/particulate calciumhydroxyapatite suspensions were prepared using a series of designatedparticle size ranges. The distribution of particles was uniform withineach range of particle sizes. The particles were smooth, round calciumhydroxyapatite, and the gel had the same constituency as Example 1. Thecalcium hydroxyapatite particles occupied 36 volume % of the suspension.The extrusion force into the air for each suspension containing eachdesignated range of particle sizes was measured using a standard 3 cubiccentimeter syringe in the same manner as in Example 3. The results aretabulated in Table 2, which follows, and demonstrate that littledifference in the extrusion force occurs as the particle size increases,as long as the particle sizes are uniform and maintained in a narrowdistribution range.

                  TABLE 2    ______________________________________    Size Distribution,                   Extrusion Force,    microns        lbs    ______________________________________    40-60          2.3    62-74          2.0    40-74          2.6     82-100        2.3    100-125        2.2    125-149        2.4    100-149        2.4    ______________________________________

EXAMPLE 5

Sodium carboxymethylcellulose, water and glycerin in various weightpercents were formulated into four different gels following theprocedure of Example 1, except for the use of different proportions.Each gel was then blended with about 40 volume % calcium hydroxyapatiteparticles having a distribution of 38 to 63 microns. The gel/particleblends were then placed in standard 3 cubic centimeter syringes fittedwith 18 gauge, 20 gauge and 22 gauge needles. The extrusion force of theblend into the air was measured in the same manner as in Example 3. Theresults appear below in Table 3.

                  TABLE 3    ______________________________________    Weight %          Force, lbs    % NaCMC*            Glycerin Water    18 gauge                                     20 gauge                                            22 gauge    ______________________________________    1.0     60       40       3.6    6.4    7.7    1.5     50       50       4.0    5.8    8.2    2.0     30       70       4.1    6.3    7.7    2.0     40       60       4.8    7.0    9.2    ______________________________________     *Sodium carboxymethylcellulose. Weight % of sodium carboxymethylcellulose     based on total weight of glycerin and water.

What is claimed is:
 1. An implantable or injectable soft tissueaugmentation material comprising a matrix of rounded, substantiallyspherical, biocompatible, substantially non-resorbable, finely dividedceramic particles close to or in contact with each other, said particleshaving a size distribution in the range from 15 μm to 150 μm.
 2. Thematerial of claim 1 wherein said ceramic particles have a surfaceporosity of less than about 30 volume percent.
 3. The material of claim1 wherein said ceramic particles have a density from about 75 to 100% oftheoretical density.
 4. The material of claim 1 wherein said particlesare greater than 15 microns in diameter.
 5. The material of claim 1wherein said particle size distribution is between about 35 and 150microns.
 6. The material of claim 1 wherein said particle sizedistribution is less than or equal to about 35 microns.
 7. The materialof claim 6 wherein said particle size distribution is less than or equalto about 20 microns.
 8. The material of claim 7 wherein said particlesizes are substantially equivalent.
 9. The material of claim 1 whereininterstitial space between said particles is maximized by employing aparticle size range, said range being defined by a lower limit and anupper limit such that the lower limit is greater than 0.4 times the meanvalue of said range.
 10. The augmentation material of claim 1 whereinthe ceramic particles comprises calcium phosphate, calcium silicate,calcium carbonate or alumina.
 11. The augmentation material of claim 10,wherein the calcium phosphate is selected from the group consisting ofcalcium hydroxyapatite, tetracalcium phosphate, calcium pyrophosphate,tricalcium phosphate, octacalcium phosphate, calcium fluoroapatite,calcium carbonate apatite, and combinations thereof.
 12. Theaugmentation material of claim 11, wherein the calcium phosphatecomprises calcium hydroxyapatite.
 13. The augmentation material of claim1, wherein the ceramic particles are homogeneously suspended in abiocompatible, resorbable fluid lubricant.
 14. The augmentation materialof claim 13, wherein the material contains ceramic particles in anamount from about 15% to 50% by volume of the total augmentationmaterial.
 15. The augmentation material of claim 13, wherein thelubricant is a gel comprising aqueous glycerin and sodiumcarboxymethylcellulose.
 16. The augmentation material of claim 15,wherein a ratio of water to glycerin in the gel varies from about 10 to100:90 to 0, respectively.
 17. The augmentation material of claim 16,wherein the ratio of water to glycerin in the gel varies from about 25to 100:75 to 25, respectively.
 18. The augmentation material of claim 15wherein said sodium carboxymethylcellulose has a viscosity from about1000 to 2800 centipoise.
 19. The augmentation material of claim 15wherein said sodium carboxymethylcellulose is present within said gel inan amount of from about 0.25 to 5 percent by weight.
 20. Theaugmentation material of claim 19 wherein said sodiumcarboxymethylcellulose is present within said gel in an amount of fromabout 1.25 to 3.25 percent by weight.
 21. An injectable implantcomposition comprising biocompatible ceramic particles present in apharmaceutically acceptable fluid carrier, wherein the ceramic particleshave been size selected to have a size distribution in the range from 15μm to 150 μm.
 22. An injectable implant composition as in claim 21,wherein the ceramic particles are composed of calcium phosphate mineral.23. An injectable implant composition as in claim 22, wherein thecalcium phosphate mineral is selected from the group consisting ofsintered hydroxyapatite and tricalcium phosphate.
 24. A method forpreparing injectable implant compositions, said method comprisingcombining ceramic particles and a pharmaceutically acceptable fluidcarrier, wherein the ceramic particles have been size selected to have asize distribution in the range from 15 μm to 150 μm.
 25. A method as inclaim 24, wherein the ceramic particles are composed of calciumphosphate mineral particles.
 26. A method as in claim 24, wherein thecalcium phosphate mineral particles are composed of a material selectedfrom the group consisting of sintered hydroxyapatite and tricalciumphosphate.
 27. A method as in claim 24, wherein the fluid carriercomprises a biocompatible organic polymer which will dissipate from atissue injection site, leaving the ceramic particles.
 28. A method as inclaim 27, wherein the organic polymer is a polysaccharide.
 29. A kitcomprising:a syringe loaded with a volume of biocompatible ceramicparticles which have been size selected to have a size distribution inthe range from 15 μm to 150 μm present in a fluid carrier.
 30. A methodfor preparing injectable implant compositions, said methodcomprising:providing a ceramic material in the form of fine particles;screening the fine particles to remove ceramic particles sized above 150μm and below 15 μm; and combining the fine particles remaining afterscreening with a pharmaceutically acceptable fluid carrier.
 31. A methodas in claim 30, wherein the ceramic particles are treated to minimizesurface porosity prior to combination with the fluid carrier.
 32. Amethod as in claim 30, wherein the ceramic particles are composed ofcalcium phosphate mineral particles.
 33. A method as in claim 32,wherein the calcium phosphate mineral particles are composed of amaterial selected from the group consisting of sintered hydroxyapatiteand tricalcium phosphate.
 34. A method as in claim 30, wherein theceramic particles are combined in the fluid carrier in an amount from 15to 50% by volume of the total composition.
 35. A method as in claim 30,wherein the fluid carrier comprises a biocompatible organic polymerwhich will dissipate from a tissue injection site, leaving the ceramicparticles.
 36. A method as in claim 35, wherein the organic polymer is apolysaccharide.
 37. A method as in claim 30, wherein the carriercomprises a biocompatible fluid lubricant.
 38. A method as in claim 37,wherein the biocompatible fluid lubricant comprises glycerin.
 39. Aninjectable implant composition comprising ceramic particles composed ofcalcium phosphate mineral and having minimized surface porosity presentin a pharmaceutically acceptable fluid carrier, wherein the ceramicparticles have been size selected to have a size distribution in therange from 15 μm to 150 μm.
 40. An injectable implant compositioncomprising biocompatible ceramic particles present in a pharmaceuticallyacceptable fluid carrier in an amount from 15 to 50% by volume of thetotal composition, wherein the ceramic particles have been size selectedto have a size distribution in the range from 15 μm to 150 μm.
 41. Aninjectable implant composition comprising biocompatible ceramicparticles present in a biocompatible organic polymer which willdissipate from a tissue injection site leaving the ceramic particles,wherein the ceramic particles have been size selected to have a sizedistribution in the range from 15 μm to 150 μm.
 42. An injectableimplant composition as in claim 41, wherein the organic polymer is apolysaccharide.
 43. An injectable implant composition comprisingbiocompatible ceramic particles and a biocompatible fluid lubricant,present in a pharmaceutically acceptable fluid carrier, wherein theceramic particles have been size selected to have a size distribution inthe range from 15 μm to 150 μm.
 44. An injectable implant composition asin claim 43, wherein the biocompatible lubricant comprises glycerin. 45.A method for preparing injectable implant compositions, said methodcomprising combining ceramic particles and a pharmaceutically acceptablefluid carrier wherein the ceramic particles have been treated tominimize surface porosity prior to combining and have been size selectedto have a size from 15 μm to 150 μm.
 46. A method for preparinginjectable implant compositions, said method comprising combiningceramic particles in a pharmaceutically acceptable fluid carrier in anamount from 15 to 50% by volume of the total composition, wherein theceramic particles have been size selected to have a size from 15 μm to150 μm.
 47. A method for preparing injectable implant compositions, saidmethod comprising combining ceramic particles and a biocompatible fluidlubricant in a pharmaceutically acceptable fluid carrier, wherein theceramic particles have been size selected to have a size from 15 μm to150 μm.
 48. A method as in claim 47, wherein the biocompatible fluidlubricant comprises glycerin.